This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Retinoids, all-trans-retinoic acid (t-RA) and 9-cis-retinoic acid (9-cis-RA), are vitamin A derivatives that mediate a variety of integral biological processes including embryogenesis, cellular differentiation, proliferation, and immune response. Retinoids elicit their effects by acting as agonists for two nuclear retinoid receptors that are ligand dependent heterodimeric transcription factors. Upon retinoid exposure, nuclear retinoid receptors augment or dampen gene expression of retinoid responsive genes, including ADAMS (a disintegrin and metalloprotease). ADAMs are multidomain proteins that are recognized as a novel class of integrin ligand and are well characterized for executing the critical function of ectodomain shedding. Current models and data attribute abnormal shedding events associated with disease states to aberrant ADAM expression levels and/or disruption of ADAM-integrin complexes. Through genetic influence, retinoids and relevant metabolites plausibly govern shedding by altering the abundance of ADAMs and thereby directly impact the extent of ADAM-integrin complexes. This proposal establishes a testable model that couples ADAMs and retinoids directly to genetic regulation through ADAM shedding of a heterodimeric partner of a retinoid receptor.